Lipoxygenases are the enzymes related to the oxydative metabolic pathway of unsaturated fatty acids. 5-, 8-, 11-, 12- and 15-lipoxygenases are rather well characterized enzymes among those enzymes. A particular lipoxygenase oxidizes a particular position of arachidonic acid to produce a particular metabolite. For example, 5(S)-lipoxygenase produces 5-HETE ((5(S)-5-hydroxyeicosa-6(E),8(Z),11(Z),14(Z)-tetraenoic acid or LTs (so called leukotrienes) through 5-HPETE (5(S)-5-hydroperoxyeicosa-6(E),8(Z),11(Z),14(Z)-tetraenoic acid).
In spite of being found in mammalian tissue the role of 12-lipoxygenase is not well known.
12(S)-HETE (12(S)-hydroxyeicosa-5(Z),8(Z),10(E), 14(Z)-tetraenoic acid), a metabolite of arachidonate, is produced by 12-lipoxygenase and possesses a variety of biological characteristics, e.g., an antagonism of LTB4 and an enhancement of the enzyme activity of 5-lipoxygenase. It is thought that 12-lipoxygenase is involved in inflammation and immunity. Further, it is also thought that lipoxygenases are closely related to ischemic heart diseases and ischemic brain diseases.
It has been reported that 12-HETE induces a chemotactic reaction of smooth muscle cells in rat (Atherosclerosis, 44, 339, 1982). It was thought that such chemotactic action of 12(S)-HETE produced by 12-lipoxygenase in plasma platelets might be related to the induction of arteriosclerosis.
Recent studies have shown that some types of cancer cells can induce aggregation of plasma platelets. Cancer cells activate plasma platelets, in such a way that metabolites of arachidonate are released. Among these metabolites, a considerable amount of 12-HETE was detected (Cancer Res., 47, 6751, 1987; ibid 47, 25, 1987).
It has been also found that a process of cancer metastasis involves adhesion of a cancer cell(s) to subendothelial matrices through receptors, the expression of which expression is enhanced by 12-HETE (Cancer Res., 49, 1029, 1989).
A 12-lipoyxgenase inhibitor inhibits the production of 12-HETE by 12-lipoxygenase. Therefore, 12-lipoxygenase inhibitor may be useful for the treatment and/or prevention of inflammation, cancer metastasis, immune diseases, psoriasis, arteriosclerosis and/or ischaemic cardiovascular diseases.